Multienzymatic Orthogonal Activation of DNA Codec Enables Tumor-Specific Imaging of Base Excision Repair Activity.

Accurate monitoring of base excision repair (BER) activity in cancer cells is critical for advancing the comprehension of DNA repair processes, gaining insights into cancer development, and guiding treatment strategies. However, current assay techniques for assessing BER activity in cancer cells face challenges due to the heterogeneous origins and diversity of BER enzymes. In this work, we present a highly reliable triple loop-interlocked DNA codec (GATED) that enables precise assessment of BER activity in cancer cells through signal amplification mediated by multienzyme orthogonal activation. The GATED device features a dumbbell-shaped DNA probe to encode two BER enzymes for BER-related signal conversion as well as two bound circular DNA to decode the apurinic/apyrimidinic sites for apurinic/apyrimidinic endonuclease 1 (APE1)-mediated signal amplification. Importantly, GATED is orthogonally activated by multiple target BER enzymes (i.e., uracil DNA glycosylase, thymine DNA glycosylase, and APE1), resulting in a unified fluorescent signal that significantly improves the detection specificity and sensitivity to BER enzymes. Additionally, we demonstrate that the GATED has exceptional biostability within complex biological systems, where it was successfully employed to monitor BER activity in cancer cells with high specificity and enabled cell-based high-throughput screening for BER inhibitors. The GATED provides a much-needed tool for the real-time monitoring of BER activity and the screening of BER inhibitors in cancer cells, potentially advancing both the investigation and clinical application of BER biology.

Dramatically elevated plasma vascular endothelial growth factor levels from influenza A infection in polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome: A case report.

We present a patient with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome who had a dramatic and sustained elevation in plasma vascular endothelial growth factor (VEGF) levels from 182 to 740 pg/mL while on lenalidomide-dexamethasone therapy. Given his biochemical evidence of progression, second-line daratumumab was added. In hindsight, a concurrent influenza A infection was the likely driver of his VEGF elevation rather than his underlying POEMS syndrome. Given the importance of longitudinal VEGF monitoring and the infectious risks of plasma cell therapies, our case highlights the need for caution with POEMS response assessments in the setting of a respiratory viral infection.

Long-Term Survival Trend of Gynecological Cancer: A Systematic Review of Population-Based Cancer Registration Data.

Gynecological cancer significantly affect the health of women. This review aimed to describe the global patterns and trends in the survival of patients with gynecological cancers. We searched PubMed, Embase, Web of Science, SinoMed, and SEER for survival analyses of cancer registration data of cervical, endometrial, and ovarian cancers published between 1980 and 2022. Globally, the highest 5-year observed survival rate for cervical cancer was 76.5% in Anshan, Liaoning, China (2008-2017). The 5-year observed survival rates of endometrial and ovarian cancers were higher in Finland (1995-1999, 82.5%) and Singapore (1988-1992, 62.0%). The 5-year relative survival rate of cervical cancer patients was higher in Haining, Zhejiang, China (2011-2014, 85.8%). Korea ranked first at 89.0% and 64.5% for endometrial and ovarian cancers, respectively. Survival rates have improved for cervical, endometrial, and ovarian cancers. Patients aged ≥ 75 years and those with advanced-stage disease had the worst 5-year survival rates. Survival rates were better for squamous cell carcinoma in cervical cancer, for endometrial carcinoma and mucinous adenocarcinoma in endometrial cancer, and for germ cell and sex-cord stromal tumors in ovarian cancer. Over the past four decades, the survival rates of gynecological cancers have increased globally, with notable increases in cervical and endometrial cancers. Survival rates are higher in developed countries, with a slow-growing trend. Future studies should focus on improving survival, especially in ovarian cancer patients.

Selective Activation of Cascade Assembly Amplification for DNA Methyltransferase Detection Using a Double-Loop Interlocked DNA Circuit.

Precise and reliable monitoring of DNA adenine methyltransferase (Dam) activity is essential for disease diagnosis and biological analysis. However, existing techniques for detecting Dam activity often rely on specific DNA recognition probes that are susceptible to DNA degradation and exhibit limited target sensitivity and specificity. In this study, we designed and engineered a stable and dynamic DNA nanodevice called the double-loop interlocked DNA circuit (DOOR) that enables the sensitive and selective monitoring of Dam activity in complex biological environments. The DOOR incorporates two interlocked specialized sequences: a palindromic sequence for Dam identification and an initiator sequence for signal amplification. In the presence of Dam, the DOOR is cleaved by double-stranded DNA phosphodiesterase I endonuclease, generating massive double-stranded DNA (dsDNA) units. These units can self-assemble into a long dsDNA scaffold, thereby enhancing the subsequent reaction kinetics. The dsDNA scaffold further triggers a hyperbranched hybrid chain reaction to produce a fluorescent 3D DNA nanonet, enabling more precise monitoring of the Dam activity. The DOOR device exhibits excellent sensitivity, specificity, and stability, rendering it a powerful tool for studying DNA methylation in various biological processes and diseases.

The Prognostic Role of Perineural Invasion for Survival in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

The aim of this study was to conduct a comprehensive review of the predictive significance of PNI in HNSCC survival outcomes. A systematic search was conducted across multiple databases, and all studies published in the last decade were screened (Research Registry ID: reviewregistry1853). The included studies were assessed using the Quality in Prognosis Studies tool. Survival outcome data were extracted, combined, and presented as hazard ratios (HR) with a 95% confidence interval (CI). Totally, 74 studies encompassing 27,559 patients were analyzed and revealed a cumulative occurrent rate of 30% for PNI in HNSCC. PNI+ HNSCC patients had a worse overall survival (HR: 1.91, 95% CI: 1.71-2.13), disease-specific survival (HR: 1.79, 95% CI: 1.55-2.07), disease-free survival (HR: 1.82, 95% CI: 1.69-1.96), local recurrence (HR: 2.54, 95% CI: 1.93-3.33), locoregional recurrence (HR: 2.27, 95% CI: 1.82-2.82), locoregional relapse free survival (HR: 1.77, 95% CI: 1.28-2.45), distant metastasis (HR: 1.82, 95% CI: 1.34-2.48), and distant metastasis-free survival (HR: 2.97, 95% CI: 1.82-4.85) compared to those PNI- patients. The available evidence unequivocally establishes PNI as a critical prognostic factor for worse survival in HNSCC patients.

Triterpene-Based Prodrug for Self-Boosted Drug Release and Targeted Oral Squamous Cell Carcinoma Chemotherapy.

Chemotherapy is one of the main treatments for oral squamous cell carcinoma (OSCC), especially as a combined modality approach with and after surgery or radiotherapy. Limited therapeutic efficiency and serious side effects greatly restrict the clinical performance of chemotherapeutic drugs. The development of smart nanomedicines has provided new research directions, to some extent. However, the involvement of complex carrier compositions inevitably brings biosafety concerns and greatly limits the "bench-to-bed" translation of most nanomedicines reported. In this study, a carrier-free self-assembled prodrug was fabricated by two triterpenes (glycyrrhetinic acid, GA and ginsenoside Rh2, Rh2) isolated from medicinal plants, licorice, and ginseng, for the targeted and highly effective treatment of OSCC. Reactive oxygen species (ROS) self-supplied molecule TK-GA2 was synthesized with ROS-responsive thioketal linker and prodrug was prepared by a rapid-solvent-exchange method with TK-GA2 and Rh2. After administration, oral tumor cells transported large amounts of prodrugs with glucose ligands competitively. Endogenous ROS in oral tumor cells then promoted the release of GA and Rh2. GA further evoked the generation of a large number of ROS to help self-boosted drug release and increase oxidative stress, synergistically causing tumor cell apoptosis with Rh2. Overall, this carrier-free triterpene-based prodrug might provide a preeminent opinion on the design of effective chemotherapeutics with low systemic toxicity against OSCC.

Nanoconfined Silver Nanoclusters Combined with X-Shaped DNA Recognizer-Triggered Cascade Amplification for Electrochemiluminescence Detection of APE1.

Apurinic/apyrimidinic endonuclease 1 (APE1), as a vital base excision repair enzyme, is essential for maintaining genomic integrity and stability, and its abnormal expression is closely associated with malignant tumors. Herein, we constructed an electrochemiluminescence (ECL) biosensor for detecting APE1 activity by combining nanoconfined ECL silver nanoclusters (Ag NCs) with X-shaped DNA recognizer-triggered cascade amplification. Specifically, the Ag NCs were prepared and confined in the glutaraldehyde-cross-linked chitosan hydrogel network using the one-pot method, resulting in a strong ECL response and exceptional stability in comparison with discrete Ag NCs. Furthermore, the self-assembled X-shaped DNA recognizers were designed for APE1 detection, which not only improved reaction kinetics due to the ordered arrangement of recognition sites but also achieved high sensitivity by utilizing the recognizer-triggered cascade amplification of strand displacement amplification (SDA) and DNAzyme catalysis. As expected, this biosensor achieved sensitive ECL detection of APE1 in the range of 1.0 × 10-3 U·µL-1 to 1.0 × 10-10 U·µL-1 with the detection limit of 2.21 × 10-11 U·µL-1, rendering it a desirable approach for biomarker detection.

A close-looped DNAzyme walker with an available catalytic domain for electrochemiluminescent detection of acetamiprid.

Traditional DNA walkers face enormous challenges due to limited biostability and reaction kinetics. Herein, we designed a self-driven close-looped DNAzyme walker (cl-DW) with high structural biostability and catalytic activity that enabled rapid electrochemiluminescence (ECL) detection of pesticide residue acetamiprid. Specifically, cl-DW exhibited increasing ability to resist nuclease degradation with a 570-fold longer half-degradation time than that of the single-stranded DNAzyme walker (ss-DW) due to the protected DNA terminal. Furthermore, cl-DW achieved high catalytic activity with a 4.3-fold faster reaction kinetic than that of ss-DW due to the circularized nanostructure of an available catalytic domain. Consequently, we utilized cl-DW as a signal amplifier and tin-based sulfide (SnS2) nanoflowers as ECL emitters to construct an ECL aptasensor, which realized the sensitive detection of acetamiprid with a limit of detection of 0.85 nM. This work provides a reliable approach to exploring DNA walkers with high catalytic activity and better biostability for molecular monitoring.

Tolerability of the niraparib individualized starting dose in the PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib first-line maintenance therapy.

PURPOSE: To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016). METHODS: The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years). RESULTS: Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia). CONCLUSION: The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety.

Random forest differentiation of Escherichia coli in elderly sepsis using biomarkers and infectious sites.

This study addresses the challenge of accurately diagnosing sepsis subtypes in elderly patients, particularly distinguishing between Escherichia coli (E. coli) and non-E. coli infections. Utilizing machine learning, we conducted a retrospective analysis of 119 elderly sepsis patients, employing a random forest model to evaluate clinical biomarkers and infection sites. The model demonstrated high diagnostic accuracy, with an overall accuracy of 87.5%, and impressive precision and recall rates of 93.3% and 87.5%, respectively. It identified infection sites, platelet distribution width, reduced platelet count, and procalcitonin levels as key predictors. The model achieved an F1 Score of 90.3% and an area under the receiver operating characteristic curve of 88.0%, effectively differentiating between sepsis subtypes. Similarly, logistic regression and least absolute shrinkage and selection operator analysis underscored the significance of infectious sites. This methodology shows promise for enhancing elderly sepsis diagnosis and contributing to the advancement of precision medicine in the field of infectious diseases.

Early Detection of Pipeline Natural Gas Leakage from Hyperspectral Imaging by Vegetation Indicators and Deep Neural Networks.

The timely detection of underground natural gas (NG) leaks in pipeline transmission systems presents a promising opportunity for reducing the potential greenhouse gas (GHG) emission. However, existing techniques face notable limitations for prompt detection. This study explores the utility of Vegetation Indicators (VIs) to reflect vegetation health deterioration, thereby representing leak-induced stress. Despite the acknowledged potential of VIs, their sensitivity and separability remain understudied. In this study, we employed ground vegetation as biosensors for detecting methane emissions from underground pipelines. Hyperspectral imaging from vegetation was collected weekly at both plant and leaf scales over two months to facilitate stress detection using VIs and Deep Neural Networks (DNNs). Our findings revealed that plant pigment-related VIs, modified chlorophyll absorption reflectance index (MCARI), exhibit commendable sensitivity but limited separability in discerning stressed grasses. A NG-specialized VI, the optimized soil-adjusted vegetation index (OSAVI), demonstrates higher sensitivity and separability in early detection of methane leaks. Notably, the OSAVI proved capable of discriminating vegetation stress 21 days after methane exposure initiation. DNNs identified the methane leaks following a 3-week methane treatment with an accuracy of 98.2%. DNN results indicated an increase in visible (VIS) and a decrease in near-infrared (NIR) in spectra due to methane exposure.

Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .

Anxiety and depression in nasopharyngeal carcinoma patients and network analysis to identify central symptoms: A cross-sectional study from a high-incidence area.

PURPOSE: To determine the prevalence of anxiety and depression in patients with nasopharyngeal carcinoma (NPC) and to identify central symptoms and bridge symptoms among psychiatric disorders. METHODS: This cross-sectional study recruited patients with NPC in Guangzhou, China from May 2022, to October 2022. The General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) were used for screening anxiety and depression, respectively. Network analysis was conducted to evaluate the centrality and connectivity of the symptoms of anxiety, depression, quality of life (QoL) and insomnia. RESULTS: A total of 2806 respondents with complete GAD-7 and PHQ-9 scores out of 3828 were enrolled. The incidence of anxiety in the whole population was 26.5% (depression, 28.5%; either anxiety or depression, 34.8%). Anxiety was highest at caner diagnosis (34.2%), while depression reached a peak at late-stage radiotherapy (48.5%). Both moderate and severe anxiety and depression were exacerbated during radiotherapy. Coexisting anxiety and depression occurred in 58.3% of those with either anxiety or depression. The generated network showed that anxiety and depression symptoms were closely connected; insomnia was strongly connected with QoL. "Sad mood", "Lack of energy", and "Trouble relaxing" were the most important items in the network. Insomnia was the most significant bridge item that connected symptom groups. CONCLUSION: Patients with NPC are facing alarming disturbances of psychiatric disorders; tailored strategies should be implemented for high-risk patients. Besides, central symptoms (sad mood, lack of energy, and trouble relaxing) and bridge symptoms (insomnia) may be potential interventional targets in future clinical practice.

Residential mobility and liver cancer risk: findings from a prospective cohort study in Chinese women.

BACKGROUND: Residential mobility is believed to influence the occurrence and development of cancer; however, the results are inconclusive. Furthermore, limited studies have been conducted on Asian populations. This study aimed to evaluate the relationship between residential mobility and liver cancer risk among Chinese women. METHODS: We enrolled 72,818 women from urban Shanghai between 1996 and 2000, and then followed them until the end of 2016. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the association between residential mobility and liver cancer risk. A linear trend test was conducted by ranking variables. A sensitivity analysis was also conducted, excluding participants with follow-up times of less than 2 years, to prevent potential bias. RESULTS: During the 1,269,765 person-years of follow-up, liver cancer was newly diagnosed in 259 patients. Domestic migration (HR = 1.47, 95% CI, 1.44-1.50), especially immigration to Shanghai (HR = 1.47, 95% CI, 1.44-1.50) was associated with an increased risk of liver cancer. In addition, migration frequency, age at initial migration and first immigration to Shanghai had linear trends with an increased liver cancer risk (Ptrend <0.001). The results were similar when excluding participants with less than two years of follow-up. CONCLUSIONS: The possible association between residential mobility and a higher risk of liver cancer in women could suggest the need for effective interventions to reduce adverse environmental exposures and enhance people's health.

Moslae Herba: Botany, Traditional Uses, Phytochemistry, and Pharmacology.

Moslae Herba (MH) can be used for both medicine and food and has a long history of medicine. MH has the effects of sweating and relieving the exterior, removing dampness and harmonizing, and is mainly used for colds caused by damp heat in summer. It is called "Xiayue Zhi Mahuang" in China. So far, 123 chemical compounds have been isolated and identified from MH, including flavonoids, terpenoids, phenolic acids, phenylpropanoids, and other chemical compounds. Its chemical components have a wide range of pharmacological activities, including antibacterial, antiviral, anti-inflammatory, antioxidant, analgesic sedation, antipyretic, immune regulation, insecticidal, and other effects. In addition, because of its aromatic odor and health care function, MH also has development and utilization value in food, chemical, and other fields. This paper reviewed the research progress of MH in botany, traditional uses, phytochemistry, and pharmacology and provided a possible direction for further research.

Dynamic surface reconstruction of individual gold nanoclusters by using a co-reactant enables color-tunable electrochemiluminescence.

Here we report for the first time the phenomenon of continuously color-tunable electrochemiluminescence (ECL) from individual gold nanoclusters (Au NCs) confined in a porous hydrogel matrix by adjusting the concentration of the co-reactant. Specifically, the hydrogel-confined Au NCs exhibit strong dual-color ECL in an aqueous solution with triethylamine (TEA) as a co-reactant, with a record-breaking quantum yield of 95%. Unlike previously reported Au NCs, the ECL origin of the hydrogel-confined Au NCs is related to both the Au(0) kernel and the Au(i)-S surface. Surprisingly, the surface-related ECL of Au NCs exhibits a wide color-tunable range of 625-829 nm, but the core-related ECL remains constant at 489 nm. Theoretical and experimental studies demonstrate that the color-tunable ECL is caused by the dynamic surface reconstruction of Au NCs and TEA radicals. This work opens up new avenues for dynamically manipulating the ECL spectra of core-shell emitters in biosensing and imaging research.

Prognostic and immunological implications of paraptosis-related genes in lung adenocarcinoma: Comprehensive analysis and functional verification of hub gene.

BACKGROUND: Lung adenocarcinoma (LUAD) poses significant clinical challenges due to its inherent heterogeneity and variable response to treatment. Recent research has specifically focused on elucidating the role of Paraptosis-related genes (PRGs) in the progression of cancer and the prognosis of patients. METHODS: We conducted a comprehensive analysis of the differential expression of PRGs in LUAD. Additionally, univariate Cox regression analysis was utilized to determine the prognostic significance of these genes. Furthermore, consensus clustering was employed to differentiate molecular subtypes within LUAD, while immune heterogeneity was assessed. To evaluate treatment outcomes, the expression of immune checkpoint inhibitors was examined, and the sensitivity of LUAD patients to chemotherapy drugs was assessed. Moreover, machine learning algorithms were employed to construct a Paraptosis-related risk score with prognostic and immunological indicators. Finally, to validate the findings, in vitro experiments were performed to verify the regulatory effect of key PRGs on Paraptosis. RESULTS: Our analysis identified 24 PRGs that exhibited differential expression, with CDKN3, TP53, and PHB emerging as the most prominently upregulated genes in tumor tissues. Among these genes, seven were identified as prognostic markers, with HSPB8 being the sole protective factor. Notably, our analysis also revealed the existence of two distinct molecular subtypes within LUAD, each characterized by unique prognoses and immune responses. Specifically, Subtype B displayed a poorer prognosis but demonstrated increased sensitivity to both chemotherapy and immunotherapy. In addition, our development of a Paraptosis-Associated Risk Score yielded a significant prognostic value in predicting patient outcomes. Furthermore, we found regulatory effect of CDKN3 on Paraptosis in two cell lines. CONCLUSIONS: Our study highlights the importance of PRGs in LUAD, particularly in prognosis and treatment response. The identified molecular subtypes and Paraptosis-Associated Risk Score offer valuable insights for personalized treatment strategies.

Genetic mechanism of body size variation in groupers: Insights from phylotranscriptomics.

Animal body size variation is of particular interest in evolutionary biology, but the genetic basis remains largely unknown. Previous studies have shown the presence of two parallel evolutionary genetic clusters within the fish genus Epinephelus with evident divergence in body size, providing an excellent opportunity to investigate the genetic basis of body size variation in vertebrates. Herein, we performed phylotranscriptomic analysis and reconstructed the phylogeny of 13 epinephelids originating from the South China Sea. Two genetic clades with an estimated divergence time of approximately 15.4 million years ago were correlated with large and small body size, respectively. A total of 180 rapidly evolving genes and two positively selected genes were identified between the two groups. Functional enrichment analyses of these candidate genes revealed distinct enrichment categories between the two groups. These pathways and genes may play important roles in body size variation in groupers through complex regulatory networks. Based on our results, we speculate that the ancestors of the two divergent groups of groupers may have adapted to different environments through habitat selection, leading to genetic variations in metabolic patterns, organ development, and lifespan, resulting in body size divergence between the two locally adapted populations. These findings provide important insights into the genetic mechanisms underlying body size variation in groupers and species differentiation.

Sex-specific impact of dietary patterns on liver cancer incidence: updated results from two population-based cohort studies in China.

PURPOSE: The associations between dietary patterns and liver cancer risk have received much attention, but evidence among the Chinese population is scarce. This study aims to update the results of two cohort studies and provide the sex-specific associations in the Chinese population. METHODS: This study was based on two cohorts from the Shanghai Men's Health Study (SMHS) and the Shanghai Women's Health Study (SWHS). Diet information was collected by validated food frequency questionnaires. Dietary patterns were derived by factor analysis. Cox regression model was utilized to estimate the hazard ratio (HR) and 95% confidence interval (CI) for associations between dietary patterns and liver cancer risk. RESULTS: During median follow-up years of 11.2 (male) and 17.1 (female) years, 427 males and 252 females were identified as incident primary liver cancer cases. In males, vegetable-based dietary pattern was inversely associated with liver cancer (HRQ4-Q1: 0.67, 95%CI 0.51-0.88, Ptrend < 0.001). Interaction analysis indicated that in males lower vegetable-based dietary pattern score and older age/medical history of chronic hepatitis combined increase the hazard of liver cancer more than the sum of them, with a 114% and 1061% higher risk, respectively. In females, the fruit-based dietary pattern was associated with a reduced risk of liver cancer (HRQ4-Q1: 0.63, 95%CI 0.42-0.95, Ptrend = 0.03). In both males and females, null associations were observed between the meat-based dietary pattern and the risk of liver cancer. CONCLUSION: A vegetable-based dietary pattern in males and a fruit-based dietary pattern in females tended to have a protective role on liver cancer risk. This study provided updated information that might be applied to guide public health action for the primary prevention of liver cancer.

Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFß Signaling.

PURPOSE: Intratumoral nerve infiltration relates to tumor progression and poor survival in oral squamous cell carcinoma (OSCC). How neural involvement regulates antitumor immunity has not been well characterized. This study aims to investigate molecular mechanisms of regulating tumor aggressiveness and impairing antitumor immunity by nerve-derived factors. EXPERIMENTAL DESIGN: We performed the surgical lingual denervation in an immunocompetent mouse OSCC model to investigate its effect on tumor growth and the efficacy of anti-PD-1 immunotherapy. A trigeminal ganglion neuron and OSCC cell coculture system was established to investigate the proliferation, migration, and invasion of tumor cells and the PD-L1 expression. Both the neuron-tumor cell coculture in vitro model and the OSCC animal model were explored. RESULTS: Lingual denervation slowed down tumor growth and improved the efficacy of anti-PD-1 treatment in the OSCC model. Coculturing with neurons not only enhanced the proliferation, migration, and invasion but also upregulated TGFß-SMAD2 signaling and PD-L1 expression of tumor cells. Treatment with the TGFß signaling inhibitor galunisertib reversed nerve-derived tumor aggressiveness and downregulated PD-L1 on tumor cells. Similarly, lingual denervation in vivo decreased TGFß and PD-L1 expression and increased CD8+ T-cell infiltration and the expression of IFNγ and TNFα within tumor. CONCLUSIONS: Neural involvement enhanced tumor aggressiveness through upregulating TGFß signaling and PD-L1 expression in OSCC, while denervation of OSCC inhibited tumor growth, downregulated TGFß signaling, enhanced activities of CD8+ T cells, and improved the efficacy of anti-PD-1 immunotherapy. This study will encourage further research focusing on denervation as a potential adjuvant therapeutic approach in OSCC. SIGNIFICANCE: This study revealed the specific mechanisms for nerve-derived cancer progression and impaired antitumor immunity in OSCC, providing a novel insight into the cancer-neuron-immune network as well as pointing the way for new strategies targeting nerve-cancer cross-talk as a potential adjuvant therapeutic approach for OSCC.